Pharmacokinetics of Rilpivirine and 24-Week Outcomes after Switching from Efavirenz in Virologically Suppressed HIV-1-Infected Adolescents

Abstract

Background

Rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor drug, could be a favourable drug for maintenance therapy in HIV-infected adolescents because it has few long-term side effects. However, data among adolescents switching from efavirenz (EFV) to RPV are limited. This study investigated the pharmacokinetics (PK), safety and efficacy of RPV in virologically suppressed HIV-1-infected adolescents after switching from EFV.

Methods

Adolescents aged 12–18 years on EFV-based antiretroviral therapy (ART) were switched from EFV to RPV (25 mg, once daily). Intensive 24-h blood samplings at 0 (pre-dose), 1, 2, 4, 5, 6, 9, 12 and 24 h were performed 4 weeks after switching. PK parameters were calculated using a non-compartmental method and compared with published data from the PAINT and pooled ECHO/THRIVE substudies. HIV RNA level was measured at weeks 12 and 24. Biochemical profiles were measured at baseline and week 24.

Results

From January to June 2016, 20 adolescents (12 male) were enrolled. Median (IQR) age was 16 (15–17) years and weight was 49 (42–59) kg. Mean (sd) AUC₂₄ _h, C₂₄ _h and C_max of RPV were 2,041 (745) ng•h/ml, 69 (29) ng/ml and 143 (65) ng/ml, respectively. Median (IQR) T_max was 5 (2–9) h. Four adolescents had C₂₄ _h <40 ng/ml. All PK parameters were comparable with published data. All adolescents remained virologically suppressed at week 24. Significant decreases in fasting total cholesterol, triglyceride and low-density lipoprotein were observed (P-value <0.05).

Conclusions

Virologically suppressed HIV-infected adolescents had adequate RPV exposure and remained virologically suppressed after switching from EFV. RPV can be used as long-term maintenance ART in HIV-infected adolescents.

References

Williams

, Churchill

, Anderson

British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 (Updated November 2013.)

HIV Med 2014; 15 Suppl 2: 1–85.

European AIDS Clinical Society (EACS) guidelines version 7.1 November 2014. (Accessed 16 April 2017.) Available from http://www.eacsociety.org/files/guidelines_english_71_141204.pdf.

World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach -2nd ed. 2016. (Accessed 16 April 2017.) Available from http://www.who.int/hiv/pub/arv/arv-2016/en/.

Kenedi

C.A.

, Goforth

H.W.

A systematic review of the psychiatric side-effects of efavirenz.

AIDS Behav 2011; 15: 1803–1818.

Clifford

D.B.

, Evans

, Yang

, Acosta

E.P.

, Ribaudo

, Gulick

R.M.

Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s).

HIV Clin Trials 2009; 10: 343–355.

Nkhoma

E.T.

, Coumbis

, Farr

A.M.

No evidence of an association between efavirenz exposure and suicidality among HIV patients initiating antiretroviral therapy in a retrospective cohort study of real world data.

Medicine (Baltimore) 2016; 95: e2480.

Mollan

K.R.

, Smurzynski

, Eron

J.J.

Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data.

Ann Intern Med 2014; 161: 1–10.

Sinxadi

P.Z.

, McIlleron

H.M.

, Dave

J.A.

Plasma efavirenz concentrations are associated with lipid and glucose concentrations.

Medicine (Baltimore) 2016; 95: e2385.

European Medicine Agency. Assessment Report Edurant International non-proprietary name: Rilpivirine. United Kingdom: European Medicine Agency Science Medicines Health; 2015. (Accessed 7 September 2016.) Available from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/002264/WC500200147.pdf.

10.

U.S. Food and Drug Administration. 2011. Edurant. ND 202-022/N-000 for TMC278 (rilpivirine) IR tablet, 25 mg. U.S. Food and Drug Administration, Rockville, MD. (Accessed 15 January 2017.) Available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf.

11.

Molina

J.M.

, Clumeck

, Orkin

Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load </= 100 000 copies/ml in the pooled ECHO and THRIVE Phase 3, randomized, double-blind trials.

HIV Med 2014; 15: 57–62.

12.

Behrens

, Rijnders

, Nelson

Rilpivirine versus efavirenz with emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected patients with HIV-1 RNA </=100,000 copies/ml: week 96 pooled ECHO/THRIVE subanalysis.

AIDS Patient Care STDS 2014; 28: 168–175.

13.

Cohen

, Wohl

, Arribas

J.R.

Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/ tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults.

AIDS 2014; 28: 989–997.

14.

Cohen

C.J.

, Molina

J.M.

, Cahn

Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the Phase 3 double-blind randomized ECHO and THRIVE Trials.

J Acquir Immune Defic Syndr 2012; 60: 33–42.

15.

van Lunzen

, Antinori

, Cohen

C.J.

Rilpivirine vs. efavirenz-based single-tablet regimens in treatment-naive adults: week 96 efficacy and safety from a randomized Phase 3b study.

AIDS 2016; 30: 251–259.

16.

Crauwels

, Vingerhoets

, Ryan

, Witek

, Anderson

Pharmacokinetic parameters of once-daily rilpivirine following administration of efavirenz in healthy subjects.

Antivir Ther 2012; 17: 439–446.

17.

Mills

A.M.

, Cohen

, Dejesus

Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens.

HIV Clin Trials 2013; 14: 216–223.

18.

Lombaard

, Bunupuradah

, Flynn

P.M.

Rilpivirine as a treatment for HIV-infected antiretroviral-naive adolescents: week 48 safety, efficacy, virology and pharmacokinetics.

Pediatr Infect Dis J 2016; 35: 1215–1221.

19.

Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. Version 2.0 November 2014. (Accessed 1 February 2017.) Available from http://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf.

20.

Crauwels

, Hoogstoel

, Vanveggel

, Yarnall

, Stevens

, Boven

Rilpivirine pharmacokinetics in HIV-1-infected adolescents: a substudy of PAINT (Phase II trial). 21st Conference on Retroviruses and Opportunistic Infections. 3–6 March 2014, Boston, MA, USA. Abstract 900.

21.

Aouri

, Barcelo

, Guidi

Population pharmacokinetics and pharmacogenetics analysis of rilpivirine in HIV-1-infected individuals.

Antimicrob Agents Chemother 2016; 61: e00899–16.

22.

Hodder

, Arasteh

, De Wet

Effect of gender and race on the week 48 findings in treatment-naive, HIV-1-infected patients enrolled in the randomized, Phase III trials ECHO and THRIVE.

HIV Med 2012; 13: 406–415.

23.

Cazanave

, Reigadas

, Mazubert

Switch to rilpivirine/emtricitabine/tenofovir single-tablet regimen of human immunodeficiency virus-1 RNA-suppressed patients, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales CO3 Aquitaine Cohort, 2012–2014.

Open Forum Infect Dis 2015; 2: ofv018.

24.

Thamrongwonglert

, Chetchotisakd

, Anunnatsiri

, Mootsikapun

Improvement of lipid profiles when switching from efavirenz to rilpivirine in HIV-infected patients with dyslipidemia.

HIV Clin Trials 2016; 17: 12–16.

25.

Gazaignes

, Resche-Rigon

, Gatey

Efficacy and safety of a switch to rilpivirine-based regimens in treatment-experienced HIV-1-infected patients: a cohort study.

Antivir Ther 2016; 21: 329–336.

26.

Aboud

, Elgalib

, Pomeroy

Cardiovascular risk evaluation and antiretroviral therapy effects in an HIV cohort: implications for clinical management: the CREATE 1 study.

Int J Clin Pract 2010; 64: 1252–1259.

27.

Crauwels

H.M.

, van Heeswijk

R.P.

, Buelens

, Stevens

, Boven

, Hoetelmans

R.M.

Impact of food and different meal types on the pharmacokinetics of rilpivirine.

J Clin Pharmacol 2013; 53: 834–840.